This invention relates to methods for the treatment of hematological malignancies that may reside in the bone marrow, particularly malignancies implicated by the expression of the CXCR4 receptor, such as multiple myeloma, using inhibitors of CXCR4. CXCR4 is known to be the receptor for the chemokine SDF-1.alpha./CXCL 12. The preferred inhibitors of this invention are those which interfere with or block the CXCR4/SDF signaling pathway in humans.
The CXCR4 receptor is typically found on hematopoietic cells that reside in the bone marrow, such as white blood cells. The CXCR4 receptor is also expressed on human multiple myeloma cells and mouse multiple myeloma cells, i.e. cells isolated from mice that spontaneously develop multiple myeloma, as well as a variety of other cell types, such as stem cells. The expression of the CXCR4 receptor on these cells is believed to be a factor in their migration to the bone marrow, and for their retention in the bone marrow, and for regulating the trafficking and homing of cells involved in the immune system.
In humans and mice, multiple myeloma cells grow preferentially in the bone marrow. These cells enter the bloodstream from their point of origin (typically a lymphoid tissue or the bone marrow itself). The cells infiltrate the bone marrow in previously unaffected bones until the bone marrow in all bones of the body become involved. The specific mechanism that allows these multiple myeloma cells to traffic from the blood to the bone marrow has not been elucidated as yet. See C. Moller et al., Leukemia, 17, pages 203-210 (2003).
Multiple myeloma is a form of cancer known to affect approximately 50,000 patients in the United States, with approximately 15,000 new patients diagnosed annually. Multiple myeloma is a hematological malignancy characterized by the clonal proliferation and accumulation of immunoglobulin-producing plasma B cells in bone marrow, causing the progressive destruction of bone tissue and bone marrow. If left untreated, the condition ultimately leads to the death of the patient.
Current treatments for multiple myeloma center on the therapeutic use of various alkylating agents, anthracyclines and corticosteroids. Typical therapeutic agents include bortezomib (Velcade™), thalidomide and lenzlidomide. These treatments typically do not cure the disease, but can effectively extend the life of the patient for 3-4 years on average. Novel therapies have also been proposed to target not only multiple myeloma cells, but also multiple myeloma/host cell interactions, as well as the bone marrow itself. These newer therapies target mechanisms whereby multiple myeloma cells grow and survive in the bone marrow, and utilize drugs such as thalidomide, thalidomide derivatives, and proteasome inhibitors. See T. Hideshima et al., Immunological Reviews, 194, pages 164-176 (2003).
A drug developed by AnorMed, Inc, designated as AMD3100, originally developed as an HIV therapeutic, has been evaluated in clinical trials for mobilizing stem cells that can be ultimately used in indications such as multiple myeloma. AMD3100 is described as a stem cell mobilizer that triggers the rapid movement of stem cells out of the bone marrow and into circulating blood by blocking the cellular receptor CXCR4. Once in the circulating blood of a subject, the stem cells can be collected for use in stem cell transplants in an attempt to restore the immune system of cancer patients who have had other treatments that previously destroyed immune cells. Typical drugs of this general description are disclosed in U.S. Pat. No. 6,825,351, issued Nov. 30, 2004, and U.S. Pat. No. 6,835,731, issued Dec. 28, 2004, the respective disclosures of which are incorporated herein by reference in their entireties.
In spite of all the recent advances made in multiple myeloma treatment, the disease remains largely incurable due, in part, to the development of tumor cell resistance to conventional therapies. Accordingly, there is currently no known cure for the disease.
It is therefore an objective of this invention to provide methods for the treatment of multiple myeloma, and other hematological malignancies that are associated with the bone marrow, using therapeutic treatments which are effective and are not impeded by drug resistance. It is a further objective of this invention to provide methods for the treatment of multiple myeloma utilizing therapies directed to interrupting the CXCR4/SDF signaling pathway of multiple myeloma cells in patients.